However, the likes of Steven Gerrard and David Villa will be involved, as will former Spurs star Robbie Keane.
The match at Dick's Sporting Goods Park in Denver, Colorado, marks the official start to Spurs' pre-season campaign as they look ahead to the upcoming Premier League season.
Read on for a full preview of what is sure to be an intriguing clash, along with a look at the key players, live streaming and television information.
Date: Wednesday, July 29
Time: 9 p.m. ET, 2 a.m. BST
TV Info: Fox Sports 1 (U.S.), Sky Sports 1 (UK)
Lampard has been replaced in the All-Stars roster by New York Red Bulls skipper Dax McCarty, who admitted to being "humbled" by the inclusion, per his club:
The full 22-man squad can be found at the MLS website and includes numerous stars who have lit up the league so far this season.
U.S. men's national team stalwarts like Clint Dempsey and Michael Bradley will also be looking to make a significant impact following their recent semi-final defeat at the CONCACAF Gold Cup.
Dempsey joins Keane as former Spurs players who will be facing their old club, and the Irishman is relishing the challenge to take on the north London outfit, per the club's website:
The All Star game is a big occasion for the league and something you see over here in basketball, baseball and NFL.
Every player in the MLS wants to be involved in this game.
This is a special one for me because it’s against Tottenham, my club, the club where I felt I made my name and had a big impact.
Everyone knows Spurs is a club very close to my heart, so this is a big deal for me.
Keane has been consistently excellent for LA Galaxy and has netted two hat-tricks recently, and Spurs will have to marshal their former man effectively if they are to neutralise his threat.
Harry Kane will likely be leading the line for Spurs in Colorado following his breakout season in the Premier League in 2014-15.
He is joined in the travelling party by Christian Eriksen, Hugo Lloris and Nacer Chadli, while newcomers Kevin Wimmer and Kieran Trippier could also be involved, per MailOnline's Simeon Gholam.
Mauricio Pochettino's men were greeted by enthusiastic supporters on their arrival in the U.S. on Sunday:
Spurs, yet again, failed to make it into the Champions League for the coming season as they finished fifth in the Premier League in 2014-15.
They have a high-quality squad but need to make good preparations in the MLS All-Stars match as they look ahead to a clash with Manchester United on the opening day of the season.
The All-Stars side will be eager to get one over on the Premier League outfit and will provide a stiff challenge.
With the amount of attacking talent on display, there should be plenty of goals to make for an entertaining match.